Priority Research Papers:
In vivo quantification and perturbation of Myc-Max interactions and the impact on oncogenic potential
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Philipp Raffeiner1, Ruth Röck1, Andrea Schraffl1, Markus Hartl1, Jonathan R. Hart2, Kim D. Janda3, Peter K. Vogt2, Eduard Stefan1 and Klaus Bister1
1 Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria
2 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA
3 Department of Chemistry, The Scripps Research Institute, La Jolla, CA
Eduard Stefan, email:
Klaus Bister, email:
Keywords: transcription factor / protein-protein interactions / biosensor / small-molecule inhibitors / cancer
Received: October 01, 2014 Accepted: October 12, 2014 Published: October 12, 2014
The oncogenic bHLH-LZ transcription factor Myc forms binary complexes with its binding partner Max. These and other bHLH-LZ-based protein-protein interactions (PPI) in the Myc-Max network are essential for the physiological and oncogenic activities of Myc. We have generated a genetically determined and highly specific protein-fragment complementation assay based on Renilla luciferase to analyze the dynamic interplay of bHLH-LZ transcription factors Myc, Max, and Mxd1 in vivo. We also applied this PPI reporter to quantify alterations of nuclear Myc-Max complexes in response to mutational events, competitive binding by the transcriptional repressor Mxd1, or perturbations by small-molecule Myc inhibitors, including recently identified potent PPI inhibitors from a Kröhnke pyridine library. We show that the specificity of Myc-Max PPI reduction by the pyridine inhibitors directly correlates with their efficient and highly specific potential to interfere with the proliferation of human and avian tumor cells displaying deregulated Myc expression. In a direct comparison with known Myc inhibitors using human and avian cell systems, the pyridine compounds reveal a unique inhibitory potential even at sub-micromolar concentrations combined with remarkable specificity for the inhibition of Myc-driven tumor cell proliferation. Furthermore, we show in direct comparisons using defined avian cell systems that different Max PPI profiles for the variant members of the Myc protein family (c-Myc, v-Myc, N-Myc, L-Myc) correlate with their diverse oncogenic potential and their variable sensitivity to the novel pyridine inhibitors.
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